PROJECT 3 - ABSTRACT Alzheimer's disease (AD) pathologic change develops in an orderly anatomic sequence but the level of pathologic change varies among and within preclinical and dementia stages of AD. Moreover, multiple pathological processes, primarily AD and cerebral microvascular disease, varyingly conspire to cause memory problems and dementia. Although very successful and critically important in research settings, and likely to remain part of tiered assessment protocols, CSF biomarkers and PET imaging are likely to encounter barriers as initial screens or serial treatment monitors for millions of people. We seek to address this anticipated barrier to health care effectiveness by developing functional MRI (fMRI)-based approaches that are informative in preclinical stages of dementia. Functional connectivity fMRI (fcMRI) studies show altered functional connectivity in the default mode network (DMN) as a marker of preclinical AD, but it is not known how specific the changes are to AD, or how predictive DMN functional connectivity is of memory decline or AD progression. Moreover, current data derive mostly from research cohorts and have not focused on the likely large contribution from cerebral microvascular disease as indicated by autopsy. Indeed, the Adult Changes in Thought (ACT) study, a community-based study of brain aging and incident dementia in the Seattle area, has demonstrated in large autopsy studies that the population-attributable risk of dementia in ACT was 45% from AD and 33% from cerebral microvascular disease. Using a cohort of ACT participants that is part of the UW ADRC Clinical Core (ACT-Plus), we will evaluate the specificity of DMN functional connectivity changes in preclinical AD, as well as MRI measures of the impact of cerebral microvascular disease. Specific Aim 1. By determining novel fcMRI correlates of preclinical AD as defined by CSF biomarkers in participants without dementia, we will test the hypothesis that functional connectivity measures can discriminate individuals with CSF profiles of AD from those without, and will compare functional connectivity measures to commonly used parameters including hippocampal volume and cortical thickness, as well as to proxy measures of regional cerebral metabolism. Specific Aim 2. By determining novel fcMRI correlates of cognitive impairment and decline in individuals without dementia at baseline, and analyzing them with respect to established and experimental leading measures of cognitive decline, we will test the hypothesis that dynamic functional connectivity, using an approach we developed, is a more sensitive and informative biomarker than existing imaging approaches or stationary functional connectivity for identifying present and predicting future cognitive impairment. When successfully completed, this Project will have determined the utility of novel fMRI approaches to brain aging and preclinical AD in a sample that more closely reflects the ultimate target population.